1. Field of the Invention
The present invention relates to isoindolinone derivatives having inhibitory activity against T-type calcium channels, pharmaceutically acceptable salts thereof, a method for the preparation thereof, and a pharmaceutical composition comprising the same as an active ingredient.
2. Description of the Related Art
A calcium channel is an ion channel with a selective permeability to the ion Ca2+ which plays a privileged role in various intracellular signal transductions. These calcium channels are typically divided into high-voltage activated calcium channels and low-voltage activated calcium channels. Of the latter T-type calcium channels are representative.
T-type calcium channels are found in the central nervous system, adrenal glomerulosa cells, the sinoatrial node, Purkinje cells of the heart and cardiac myocyte membranes. T-type calcium channel blockers are known to show the effective treatment of cerebral diseases, such as epilepsy, hypertension, etc., and heart diseases such as angina pectoris [1) Hosravani, Houman et al., “Effects of Cav3.2 channel mutations linked to idiopathic generalized epilepsy”, Annals of Neurology (2005), 57(5), 745-749; 2) Vitko, Iuliia et al., “Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNAlH, a T-type calcium channel”, Journal of Neuroscience (2005), 25(19), 4844-4855; 3) Clozel, Cardiovas Drugs Ther. (1990), 4, pp. 731-736; 4) Hefti, Arzneimittelforschung (1990), 40, 417-421; 5) Moosmang, Sven et al., “Antihypertensive Effects of the Putative T-Type Calcium Channel Antagonist Mibefradil Are Mediated by the L-Type Calcium Channel Cav1. 2”, Circulation Research (2006), 98(1), 105-110]. Recently, T-type calcium channel blockers have been reported to have therapeutic effects on chronic pains [Drugs of the Future (2005), 30(6), 573-580]. For example, the T-type calcium channel blockers mibefradil and ethosuximide were shown to inhibit mechanically and thermally induced pain in a dose-dependent manner in a spinal nerve ligation model, indicating that T-type calcium channel blockers are useful in the treatment of neuropathic pain [1) Barton, Matthew E. et al., “The antihyperalgesic effects of the T-type calcium channel blockers ethosuximide, trimethadione, and mibefradil”, European Journal of Pharmacology (2005), 521, 79-85; 2) Flatters, Sarah J. L., “T-type calcium channels: A potential target for the treatment of chronic pain”, Drugs of the Future (2005), 30(6), 573-580; 3) Flatters, Sarah J. L. et al., “Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy”, Pain (2004), 109, 150-161; 4) Dogrul, Ahmet et al., “Reversal of experimental neuropathic pain by T-type calcium channel blockers”, Pain (2003), 105, 159-168]. In addition, calcium, serving as a messenger of signal transduction, regulates various cellular functions. Since cell growth is among the cellular functions in which calcium is involved, it is expected that T-type calcium channel blockers show anti-cancer effects [Nat. Rev. Mol. Cell Biol. 2003, 4, 517-529].
Mibefradil, belonging to a group known as T-type calcium channel blockers, has recently been a drug for the treatment of hypertension and chronic angina pectoris, but is now prohibited from being marketed due to the potential for drug interactions, some of them serious, which may occur which it is taken together with certain other medications. Therefore, there is an imperative requirement for the development of a novel T-type calcium channel blocker.
In spite of extensive efforts, selective T-type calcium channel blockers have rarely been developed. Compounds capable of functioning as T-type calcium channel blockers are disclosed in Korean Patent Nos. 784,195 and 754,325 with a backbone of quinazoline therefor, in Korean Patent No. 616,099 with a backbone of isoxazole therefor, and in Korean Patent No. 743,255 with a backbone of 1,3-dioxoisoindone therefor.
However, there is still a need for selective T-cell calcium channel blockers that show properties in terms of pharmacokinetic profile and ADME (absorption, distribution, metabolism and excretion) disposition and are useful in the treatment of relevant diseases, such as hypertension, cancer, epilepsy and neuropathic pain.